Baluk Peter, Adams Alicia, Phillips Keeley, Feng Jennifer, Hong Young-Kwon, Brown Mary B, McDonald Donald M
Department of Anatomy, the Cardiovascular Research Institute, and the Comprehensive Cancer Center, University of California, San Francisco, California.
Department of Anatomy, the Cardiovascular Research Institute, and the Comprehensive Cancer Center, University of California, San Francisco, California.
Am J Pathol. 2014 May;184(5):1577-92. doi: 10.1016/j.ajpath.2014.01.021. Epub 2014 Mar 11.
Lymphatics proliferate, become enlarged, or regress in multiple inflammatory lung diseases in humans. Lymphatic growth and remodeling is known to occur in the mouse trachea in sustained inflammation, but whether intrapulmonary lymphatics exhibit similar plasticity is unknown. We examined the time course, distribution, and dependence on vascular endothelial growth factor receptor (VEGFR)-2/VEGFR-3 signaling of lung lymphatics in sustained inflammation. Lymphatics in mouse lungs were examined under baseline conditions and 3 to 28 days after Mycoplasma pulmonis infection, using prospero heomeobox 1-enhanced green fluorescence protein and VEGFR-3 as markers. Sprouting lymphangiogenesis was evident at 7 days. Lymphatic growth was restricted to regions of bronchus-associated lymphoid tissue (BALT), where VEGF-C-producing cells were scattered in T-cell zones. Expansion of lung lymphatics after infection was reduced 68% by blocking VEGFR-2, 83% by blocking VEGFR-3, and 99% by blocking both receptors. Inhibition of VEGFR-2/VEGFR-3 did not prevent the formation of BALT. Treatment of established infection with oxytetracycline caused BALT, but not the lymphatics, to regress. We conclude that robust lymphangiogenesis occurs in mouse lungs after M. pulmonis infection through a mechanism involving signaling of both VEGFR-2 and VEGFR-3. Expansion of the lymphatic network is restricted to regions of BALT, but lymphatics do not regress when BALT regresses after antibiotic treatment. The lung lymphatic network can thus expand in sustained inflammation, but the expansion is not as reversible as the accompanying inflammation.
在人类多种炎症性肺病中，淋巴管会增殖、肿大或消退。已知在小鼠气管持续炎症中会发生淋巴管生长和重塑，但肺内淋巴管是否表现出类似的可塑性尚不清楚。我们研究了持续炎症中肺淋巴管的时间进程、分布以及对血管内皮生长因子受体（VEGFR）-2/VEGFR-3信号传导的依赖性。使用prospero同源框1增强绿色荧光蛋白和VEGFR-3作为标记物，在基线条件下以及肺炎支原体感染后3至28天对小鼠肺内的淋巴管进行检查。在第7天可见淋巴管芽生血管生成。淋巴管生长局限于支气管相关淋巴组织（BALT）区域，产生VEGF-C的细胞散在于T细胞区。感染后肺淋巴管的扩张通过阻断VEGFR-2减少了68%，通过阻断VEGFR-3减少了83%，通过同时阻断两种受体减少了99%。抑制VEGFR-2/VEGFR-3并不能阻止BALT的形成。用土霉素治疗已建立的感染会使BALT消退，但不会使淋巴管消退。我们得出结论，肺炎支原体感染后小鼠肺内会通过涉及VEGFR-2和VEGFR-3信号传导的机制发生强烈的淋巴管生成。淋巴管网的扩张局限于BALT区域，但抗生素治疗后BALT消退时淋巴管不会消退。因此，肺淋巴管网在持续炎症中可以扩张，但这种扩张不像伴随的炎症那样可逆。
